INVENTION FIELD
The present invention relates to pharmaceutical compositions that contain acid
salts of thienopyridine derivatives and are stabilized without having recourse to
any antioxidant agent.
INVENTION BACKGROUND
Oxidative Decomposition
The oxidative decomposition of pharmaceutical compounds is responsible for the
instability of a great number of pharmaceutical preparations. These reactions are
mediated by free radicals or by molecular oxygen. The more general form of
oxidative decomposition occurring in pharmaceutical compositions is a self-oxidation
process involving a free radical mechanism of chain reactions. In
general, a self-oxidation may be defined as the reaction of any compound with
molecular oxygen.
Free radicals are produced by reactions involving rupture of a covalent bond in
such a way that each involved atom or group retains one of the electrons of the
original covalent bond. These radicals are strongly insaturated and quickly gain
electrons from other compounds and cause their oxidation. The starting of the
reaction may be produced by thermal decomposition of the compounds which are
present or are added or by light. The reaction may be stopped by combining two
different radicals or by means of a free radical inhibitor such as sodium
metabisulfite. In the self oxidative reactions, only a very little amount of oxygen is
necessary to start the reaction and therefore the oxygen concentration will be not
important. The heavy metals, particularly those having two or more oxidation
states and distant redox potentials, usually catalyse the oxidative deteriorations.
Their main function is to increase the free radical formation rate.
Antioxidants
Antioxidants make a group of excipients that are used in medicaments in order to
decrease the oxidation of active compounds and/or excipients in a ready product.
Three types of antioxidantes are known:
- Real antioxidants - they block the chain reaction reading with the free radicals
and forming stable or metastable products and stopping the oxidation reaction;
- Reducing agents - they have a lower oxidation potential than the active
compound or excipient they protect, being therefore preferably oxidised;
- Synergistical antioxidants - they have a small antioxidant effect in themselves,
but they increase the action of other antioxidants because they form complexes
with the heavy metal ions which otherwise would catalyse the oxidation.
Examples of chelant agents are ethylenediaminetetraacetic acid (EDTA) derivatives
and salts and citric and tartaric adds.
Thienopyridines
Thienopyridines, particularly Ticlopidine, have inhibitory properties at the level of
certain plateletary and erythrocitary functions and can interfere in the arterial and
veiny thrombosis since they decrease the platelet aggregation.
Due to the possibility of suffering oxidation processes implying a therapeutical
potential decrease, some compositions have been prepared which contain
antioxidant agents with the aim of protecting the molecule against the oxidative
degradation.
The compositions containing Ticlopidine hydrochloride as described by U.S.
Patent No. 4,051,141, are liable to a discoloration process due to Ticlopidine
degradation during the storage period.
Portuguese Patent No. 73442 describes pharmaceutical compositions containing
acid salts of thienopyridine derivatives which are stabilized by antioxidant and
chelating agents, namely, non volatile and non toxic acids having a pKa of 2-6.
However, the prevention of the ready product discoloration will be not the only
reason for including antioxidant agents in a formulation.
Recently, the European Agency for Evaluating Medicinal Products published
guidelines about antioxidant use, in the publication "Note for Guidance on
Inclusion of Antioxidant and Antimicrobial Preservatives in Medicinal Products".
(CPMP/CVMP/QWP/115/95) that took effect in January 1998.
According to this document, the use of antioxidants must be restrained taking in
consideration both following principles:
1. Antioxidants should not be used to mask unsatisfactorily formulated or packed
products. 2. Antioxidants must be included in a formulation if it is proofed that their use can
not be avoided.
Therefore, the accomodation of the pharmaceutical compositions containing
antioxidants to said guideline "Note for guidance or inclusion of Antioxidantes
and Antimicrobial Preservatives in Medicinal Products" (CPMP/CVMP/QWP/115/95)
requires the demonstration that the oxidation factors can not be
eliminated.
DETAILED DISCLOSURE OF THE INVENTION
The preparation of pharmaceutical compositions with the purpose of providing an
easy administration way for an active compound accurate dose, nearly always
requires the use of adjuvants having the functions of making feasible the industrial
production, providing stability to the active compound during a tong period of
time and therefore ensuring the maintenance of the therapeutic effect, and making
easier the availability of the active compound to the necessary site. These
adjuvants, generally called excipients, as a general rule, are inert and unprovided
of therapeutical activity; therefore, their amounts preferably have to be not higher
than the necessary to obtain the desired effects.
The aim of the development work to obtain the pharmaceutical compositions that,
are the object of this invention was the confirmation of the oxidation factors for
the thienopyridine derivatives and, afterwards, to withdraw them from the
formulation so that stable compositions are obtained without adding any
antioxidant and the previously mentioned guideline is satisfied (Note for Guidance
on Inclusion of Antioxidantes and Antimicrobial Preservatives in Medicinal
Products - CPMP/CVMP/QWP/115/95). This methodology makes possible
avoiding the use of antioxidants solely for masking the presence of oxidation
factors, a common characteristic of prior art formulations. The pharmaceutical
compositions of the present invention are therefore new since it is not necessary to
have recourse to any antioxidant.
It was found that, in the presence of oxygen saturated solutions and solar light,
Ticlopidine hydrochloride undergoes an oxidative process, macroscopically
appearing a discoloration. This reaction of Ticlopidine hydrochloride oxidation
and discoloration is also observed in the presence of some excipients, as it was
shown by binary mixtures under stress conditions. The presence of certain
commonly used excipients, such as polyvinylpyrrolidone (providone), magnesium
stearate, and polyethylene glycols, promotes a discoloration associated to the
oxidative degradation of the Ticlopidine hydrochloride. However, the addition of
an antioxidant such as citric acid is capable of avoiding this discoloration, even in
the presence of these excipients.
Taking as a basis the results of the preliminary tests, the behaviour of the
Ticlopidine hydrochloride under the absence of potential agents responsible for
the oxidation (such as providone, magnesium stearate, and polyethylene glycols)
was studied.
It was concluded that, provided that these agents are not present, it is possible to
obtain stable formulations not using any antioxidant.
Thus, the results show that the use of non volatile organic acids, such as citric
acid, counteracts the disadvantageous effects of some excipients. However, if
these excipients are not included, the inclusion of said antioxidant may also be
suppressed.
In order to satisfy the rules of "Note for Guidance or Inclusion of Antioxidantes
and Antimicrobial Preservatives in Medicinal Products" (CPMP/CVMP/QWP/115/95),
it was necessary to develop a technologically feasible and stable
formulation not using the above mentioned excipients. Thus, another novelty of
this invention is the association on the same formulation of Ticlopedine
hydrochloride and alternative excipients having identical functions but being
unprovided of oxidative action, such as non metallic lubricants, non polymeric
binders and, in the coating, plasticizers not included in the polyethylene glycol
group. Another novelty of the present (invention which is also an advantage
thereof) is the use of water as the granulating and coating liquid which reduces the
process costs, is not dangerous and does not cause environmental contamination.
EXAMPLES
This invention may be illustrated by the below non limitative examples:
Example 1 - Preparation of Tablets by Wet Granulation
Components
|
Quantitative Composition (mg)
|
Effect
|
Ticlopidine hydrochloride |
250.0 |
Active compound |
Maize starch |
77.8 |
Diluent/Binder |
Microcrystalline cellulose |
43.3 |
Diluent |
Talc |
5.1 |
Lubricant |
Hydrogenated vegetable oil |
3.8 |
Lubricant |
Total
|
380.0
|
The Ticlopidine hydrochloride, 80% of the maize starch and all the
microcrystalline cellulose are blended together.
A starch decoction is prepared from the remaining starch and is slowly added to
the mixture under agitation. The uniformly wetted mixture is granulated through a
1.6 mm opening sieve. The granules are dried at 40°C to a humidity content < 5%
and screened through a 1.0 mm opening sieve. At last, the talc and the hydrogenated
vegetable oil are added and blended. The obtained granules have
rheological and technological properties suitable for the compression and make
possible the production of tablets acceptable under the technological and
pharmaceutical points of view, particularly as it concerns the uniformity, content
and release of the active compound.
Example 2 - Preparation of Coated Tablets
Components
|
Quantitative Composition (mg)
|
Ticlopidine hydrochloride |
250.000 |
Maize starch |
54.000 |
Microcrystalline cellulose |
57.000 |
Talc |
15.200 |
Hydrogenated vegetable oil |
3.800 |
Hydroxypropyl methylcellulose |
3.750 |
Triacetin |
.350 |
Titanium dioxide |
1.875 |
Total
|
386.000
|
The Ticlopidine hydrochloride, 70% of the maize starch and 90% of the
microcrystalline cellulose are blended together. The remaining starch is used to
prepare a starch decoction which is slowly added to the mixture under agitation.
The uniformly wetted mixture is granulated through a 1.6 mm opening sieve. The
granules are dried at 50°C to a humidity content < 5% and screened through a 1.0
mm opening sieve. The remaining microcrystalline cellulose, the talc and the
hydrogenated vegetable oil are added and mixed; the granules are compressed. At
last, the cores are coated by application of an aqueous suspension containing the
hydroxypropyl methylcellulose, triacetin and titanium dioxide. The intermediate
products and the coated tablets are acceptable under the technological and
pharmaceutical points of view, particularly as it concerns the uniformity, content
and release of the active compound.
Example 3 - Preparation of Ticlopidine Hydrochloride Tablets
Components
|
Quantitative Composition (mg)
|
Function
|
Ticlopidine hydrochloride |
250.0 |
Active compound |
Maize starch |
67.7 |
Diluent/Binder |
Microcrystalline cellulose |
43.3 |
Diluent |
Hydrogenated vegetable oil |
19.0 |
Lubricant |
Total
|
380.0
|
The Ticlopidine hydrochloride, 80% of the maize starch and all the
microcrystalline cellulose are blended together. A starch decoction is prepared
from the remaining starch and slowly added to the mixture under agitation. The
granules are dried at 40°C to a humidity content < 5% and screened through a 1.0.
mm opening sieve. At last, the hydrogenated vegetable oil is added and blended.
The thus obtained granules have rheological and technological properties suitable
for the compression and make possible the production of tablets acceptable under
the technological and pharmaceutical points of view, particularly as it concerns
the uniformity, content and release of the active compound.
Example 4 - Preparation of Coated Tablets
Components
|
Quantitative Composition (mg)
|
Ticlopidine hydrochloride |
250.000 |
Maize starch |
67.700 |
Microcrystalline cellulose |
43.300 |
Hydrogenated vegetable oil |
19.300 |
Hydroxypropyl methylcellulose |
3.750 |
Triacetin |
.375 |
Titanium dioxide |
1.875 |
Total
|
386.000
|
The Ticlopidine hydrochloride, 70% of the maize starch and 90% of the
microcrystalline cellulose are blended together. The remaining starch is used to
prepare a starch decoction and this is slowly added to the mixture under agitation.
The uniformly wetted mixture is granulated through a 1.6 mm opening sieve. The
granules are dried at 50°C to a humidity content < 5% and screened through a 1.0
mm opening sieve. The remaining microcrystalline cellulose, the talc and the
hydrogenated vegetable oil are added and blended; the granules are compressed.
At last, the cores are coated by applying an aqueous suspension containing the
hydroxypropyl methylcellulose, triacetin and titanium dioxide. The intermediate
products and the coated tablets are acceptable under the technological and
pharmaceutical points of view, particularly as it concerns the uniformity, content
and release of the active compound.
The coated tablets, prepared according to Examples 2 and 4, were packed in a
suitable packaging and their stability tested. The obtained results show that it is
possible to obtain stable Ticlopidine hydrochloride formulations free of any
antioxidant.
40°C/ 75% RH |
Time (month) | Dosage (%) | Dissolution (%) |
0 | 98.9 | 101 |
2 | 96.9 | 105 |
3 | 98.6 | 110 |
4 | 98.2 | 103 |
5 | 96.3 | - |
6 | 98.1 | 100 |
REFERENCES
1. Note for Guidance of Inclusion of Antioxidants and Antimicrobial Preservatives
in Medicinal Products.
CPMP/CVMP/QWP/115/95
2. An Overview of Antioxidant, Preservative and Solvent Excipients Used in the
Pharmaceutical Industry.
3. The Theory and Practice of Industrial Pharmacy, 780-784.
4. Florence, A.T.; Attwood, D (1988). Physicochemical Principles of Pharmacy.
2nd Edtion, 420-426.